- Synthesis and pharmacokinetic profile of rhein- boswellic acid conjugate
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Rhein, an active metabolite of diacerein, down-regulates the gene-expression and production of pro-matrix metalloproteinases and up-regulates the tissue inhibitors of metalloproteinase-1 production. The therapeutic effects of diacerein on osteoarthritis are, at least in part, due to the chondroprotective effect of rhein. Boswellic acid is a specific, non-redox inhibitor of leukotriene synthesis. It is claimed to possess good anti-inflammatory, anti-arthritic, analgesic, and anti-ulcer activities. It prevents the destruction of articular cartilage by decreasing degradation of glycosaminoglycans. Therefore, rhein and boswellic acid were linked chemically through a bioreversible ester linkage to synthesize their mutual prodrug by reported procedure. In vitro release profile of this prodrug was extensively studied in aqueous buffers of varied pH, upper GIT homogenates and 80% human plasma. In vivo release studies were undertaken in blood, urine and feces of rats. The prodrug was stable in HCl buffer (pH 1.2) and stomach homogenates of rats. However; in phosphate buffer (pH 7.4) and in intestinal homogenates the prodrug exhibited 91% and 96% release of rhein and 27.5% and 38% release of boswellic acid respectively over a period of 6 h following first order kinetics. In 80% human plasma (in vitro) and rat blood (in vivo) also 96.35% and 91% release of rhein and 78% and 86.41% release of boswellic acid respectively was observed. The 24 h pooled samples of rat urine revealed presence of 6.2% intact prodrug, 7.1% of rhein and 8.9% of boswellic acid indicating their renal excretion. Samples of rat feces pooled over a period of 24 h showed absence of rhein and presence of 3.1% of intact boswellic acid and 4.6% of boswellic acid emphasizing their intestinal excretion. The in vivo release kinetics of prodrug in rat clearly indicated activation of prodrug to be occurring in blood, being catalyzed by the weak alkaline pH of blood (7.4) in combination with esterases present therein.
- Suneela, Dhaneshwar,Dipmala, Patil
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Read Online
- A biocatalytic approach towards the preparation of natural deoxyanthraquinones and their impact on cellular viability
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Herein, a two-step chemoenzymatic process for the synthesis of medicinally important 3-deoxygenated anthra-9,10-quinones is developed. It involves a regio- and stereoselective reduction of hydroanthraquinones to (R)-configured dihydroanthracenones using an anthrol reductase of T. islandicus, followed by oxidation and dehydration to obtain deoxyanthraquinones in 65-80% yield. Comparison of the cell viability of normal human kidney HEK293 cells between anthraquinones and their deoxy derivatives revealed less toxicity for the latter.
- Das, Kiran,De, Arijit,Husain, Syed Masood,Maity, Biswanath,Mondal, Amit,Rajput, Anshul
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p. 3087 - 3090
(2022/02/21)
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- Synthesis of rhein and diacerein: a chemoenzymatic approach using anthrol reductase of Talaromyces islandicus
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Herein, we report two methods for the synthesis of the osteoarthritis drug rhein and its prodrug diacerein using a chemoenzymatic approach. The strategy relies on the use of an NADPH-dependent anthrol reductase of Talaromyces islandicus (ARti-2), which mediates the regioselective and reductive deoxygenation of anthraquinones. The work further implies similar biosynthesis of rhein in fungi.
- Rajput, Anshul,Mondal, Amit,Pandey, Satyendra Kumar,Husain, Syed Masood
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supporting information
p. 358 - 361
(2022/01/20)
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- Industrial production method suitable for diacerein
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The invention discloses an industrial production method suitable for diacerein. A compound as shown in a formula I is obtained after carrying out secondary oxidation on raw materials. The industrial production disclosed by the invention overcomes the disadvantages of excessive heavy metal, serious pollution, and inflammability and explosibility of a finished product prepared through a synthesis route reported in existing literatures; a reagent used by the industrial production method is low in cost, environment pollution is small, the operation is easy, and the industrial production method issuitable for industrial production; a product is good in quality, total impurities are less, the content of single impurity is controlled to be 0.1 percent or less, the finished product is controlledto be in a single and stable crystal form, and the requirements of medicinal-class bulk drugs can be met.
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Paragraph 0035-0037; 0046-0048; 0057-0059; 0068; 0069; 0070
(2018/07/30)
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- Synthetic process of rhein
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The invention relates to a total synthetic process of rhein. The synthetic process comprises the steps of: performing diene synthesis on juglone and 3-M-1-(methoxy)-1,3-butadiene to obtain a mixture,performing refining, and conducting hydrolysis to obtain rhein.
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Paragraph 0018
(2018/03/26)
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- Bis(methoxypropyl) ether-promoted oxidation of aromatic alcohols into aromatic carboxylic acids and aromatic ketones with O2 under metal- and base-free conditions
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We describe an eco-friendly, practical and operationally simple procedure for the bis(methoxypropyl) ether-promoted oxidation of aromatic alcohols into aromatic carboxylic acids and aromatic ketones with atmospheric dioxygen as the sole oxidant. This chemical process is clean with high conversion and good selectivity, and an external initiator, catalyst, additive and base are not required. The virtue of this reaction is highlighted by its easily available and economical raw materials and excellent functional group tolerance (acid-, base- and oxidant-labile groups).
- Liu, Kai-Jian,Jiang, Si,Lu, Ling-Hui,Tang, Ling-Li,Tang, Shan-Shan,Tang, Hai-Shan,Tang, Zilong,He, Wei-Min,Xu, Xinhua
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supporting information
p. 3038 - 3043
(2018/07/13)
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- Total synthesis process of rhein
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The invention relates to a total synthesis process of rhein. The process includes: adopting methoxy phthalic anhydride and a Grignard reaction liquid as the raw materials, and carrying out condensation, dehydration cyclization, methoxylation, oxidation and demethylation reaction so as to obtain rhein.
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- Spectroscopic characterization of both aqueous and solid-state diacerhein/hydroxypropyl-β-cyclodextrin inclusion complexes
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Diacerhein, a poorly water soluble antirheumatic prodrug, was spectroscopically characterized to form inclusion complexes with hydroxypropyl-β-cyclodextrin (HPβCD) in both aqueous solution and in solid phase. Complexation with the hydrophilic carriers was used to improve the solubility and dissolution rate of the compound. The kinetics of the prodrug degradation to the active rhein in aqueous buffer solution were also investigated as a function of HPβCD concentration. The solid complexes prepared by different methods such as physical mixture, kneading, co-evaporation method and freeze dried method in 1:1 M ratio, were characterized by DSC and FTIR. The dissolution profiles of solid complexes were determined and compared with diacerhein alone and their physical mixture, in the simulated intestinal fluid at 37 C. The accurate molecular spectroscopic characterization of diacerhein in the presence of different amounts of aqueous cyclodextrins was essential to determine the correct binding constants for the diacerhein/HPβCD system. The binding constants were also validated by UV spectrometry and HPLC procedure in order to compare the values from the different methods. Higuchi-Connors phase solubility method has proved not suitable when either the free or/and the complexed prodrug degrade in aqueous solution.
- Petralito, Stefania,Zanardi, Iacopo,Spera, Romina,Memoli, Adriana,Travagli, Valter
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p. 355 - 360
(2014/04/03)
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- Design, synthesis and molecular modeling of aloe-emodin derivatives as potent xanthine oxidase inhibitors
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A series of aloe-emodin derivatives were synthesized and evaluated as xanthine oxidase inhibitors. Among them, four aloe-emodin derivatives showed significant inhibitory activities against xanthine oxidase. The compound 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carbaldehyde (A1) possessed the best xanthine oxidase inhibitory activity with IC50 of 2.79 μM. Lineweaver-Burk plot analysis revealed that A1 acted as a mixed-type inhibitor for xanthine oxidase. The docking study revealed that the molecule A1 had strong interactions with the active site of xanthine oxidase and this result was in agreement with kinetic study. Consequently, compound A1 is a new-type candidate for further development for the treatment of gout.
- Shi, Da-Hua,Huang, Wei,Li, Chao,Liu, Yu-Wei,Wang, Shi-Fan
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p. 289 - 296
(2014/03/21)
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- Synthesis, biological evaluation and molecular modeling of aloe-emodin derivatives as new acetylcholinesterase inhibitors
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A series of aloe-emodin derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors. Most of the new prepared compounds showed remarkable acetylcholinesterase inhibitory activities. Among them, the compound 1-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) methyl) pyridin-1-ium chloride (C3) which has a pyridinium substituent possessed the best inhibitory activity of acetylcholinesterase (IC50 = 0.09 μM). The docking study performed with AUTODOCK demonstrated that C3 could interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of acetylcholinesterase.
- Shi, Da-Hua,Huang, Wei,Li, Chao,Wang, Ling-Ting,Wang, Shi-Fan
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p. 1064 - 1073
(2013/03/14)
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- Process for the preparation of pure diacetylrhein (diacerein)
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The present invention is directed to a process for producing pure Diacetylrhein (Diacerein), comprising the transformation of raw Diacerein or raw Rhein, into a water-soluble salt thereof, and then elimination of the impurities by passage through a hydrophobic resin: adsorption of the products, washing and then elution. After acidification of the pure salt of Diacerein or Rhein obtained after the passage through said hydrophobic resin, Diacerein is recovered and dried in a pure form. The invention is also directed to pure Diacerein obtained by the process of the invention, in which the total content of impurities is between 0 and 100 ppm. The invention is also directed to pure Diacerein obtained by the process of the invention, in which the Aloemodine content is less than 100 ppm
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Page/Page column 6-7
(2010/07/03)
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- Methods for treating leukemia and myelodysplastic syndrome, and methods for identifying agents for treating same
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The present disclosure relates to methods for treating leukemia, pre-leukemic conditions, as well as myelodysplastic syndrome and acute myelogenous leukemia. The present disclosure further relates to compounds that can be used for treating leukemia, pre-leukemic conditions, as well as myelodysplastic syndrome and acute myelogenous leukemia. The present disclosure also relates to methods for identifying compounds that can be used for treating leukemia, pre-leukemic conditions, as well as myelodysplastic syndrome.
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- Highly selective three-step synthesis of rhein in chloroaluminate molten salt: preclusion of the Hayashi rearrangement
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An expeditious, three-step synthesis of rhein (2) was optimized starting from bis(N, N-diethyl)-5-methoxybenzene-1,3-dicarboxamide. The key final step, involving deprotection/cyclization of orihobenzoylbenzoic acid 9 in acidic chloroaluminate molten salts
- Gonnot, Vanessa,Antheaume, Cyril,Nicolas, Marc,Mioskowski, Charles,Baati, Rachid
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experimental part
p. 6205 - 6210
(2010/03/24)
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- PROCESS FOR PREPARING RHEIN
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Process for the preparation of rhein or diacerein comprising oxidising aloe-emodin with hydrogen peroxide or an alkali-metal peroxide oxidant in a basic reaction medium, optionally in the presence of an organic solvent, to obtain rhein. Optionally followed by acetylating the rhein thus obtained using an acetylating agent to obtain diacerein.
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Page/Page column 12-13
(2009/10/21)
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- RHEIN CONJUGATES, PREPARATION METHOD THEREOF AND THEIR USES IN PRODUCING MEDICINES FOR TREATING DIABETIC NEPHROSIS, INTESTINAL ADHESION AND OSTEOARTHRITIS
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The conjugates of present invention are formed by the combination of rhein or their analogues with the organic bases or amino acids in molecular force between them. The methods for preparing the conjugates and their uses for manufacturing medicines in the treatment of diabetic nephrosis, recovery of gastrointestinal function and prevention of intestinal adhesion, as well as treatment of osteoarthritis, rheumatic arthritis and rheumatoid arthritis are also described. Rhein or their analogues as the left part of general formula (I) is selected from (1) the compounds of rhein or their analogues, in which one or two substituents of R2~R3 and R6~R7 are COOH at least two substituents of R1~8 are -H; or (2) the rhein-containing extract derived from plants. In general formula (I), M represents nitrogen-containing organic bases or basic amino acids.
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Page/Page column 10
(2008/06/13)
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- Rhein Conjugates, Preparation Method Thereof and Their Uses in Producing Medicines for Treating Diabetic Nephrosis, Intestinal Adhesion and Osteoarthritis
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The conjugates of present invention are formed by the combination of rhein or their analogues with the organic bases or amino acids in molecular force between them. The methods for preparing the conjugates and their uses for manufacturing medicines in the treatment of diabetic nephrosis, recovery of gastrointestinal function and prevention of intestinal adhesion, as well as treatment of osteoarthritis, rheumatic arthritis and rheumatoid arthritis are also described. Rhein or their analogues as the left part of general formula (I) is selected from (1) the compounds of rhein or their analogues, in which one or two substituents of R2?R3 and R6?R7 are COOH at least two substituents of R1?8 are —H; or (2) the rhein-containing extract derived from plants. In general formula (I), M represents nitrogen-containing organic bases or basic amino acids.
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Page/Page column 7
(2008/12/08)
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- Total synthesis of rhein and diacerhein via a directed ortho metalation of an aromatic substrate
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An efficient total synthesis of rhein and diacerhein has been accomplished by relying on a remarkable regioselective directed ortho metalation (DOM) followed by a one-pot two step addition-cyclization reaction, generating phthalide 5 intermediate efficiently.
- Gonnot, Vanessa,Tisserand, Steve,Nicolas, Marc,Baati, Rachid,Mioskowski, Charles
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p. 7117 - 7119
(2008/03/11)
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- PROCESS FOR PREPARING ALOE-EMODIN
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A process for preparing aloe-emodin from aloin by oxidizing aloin by treatment with an oxygen-containing gas in the presence of an acid. The aloe-emodin may be used for the production of rhein and diacerein by oxidizing aloe-emodin by treatment with a chromium-free oxidizing medium to obtain rhein and purifying the rhein obtained. The rhein may be acetylated to obtain diacerein.
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Page/Page column 18
(2008/06/13)
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- ESTER DERIVATIVES OF RHEIN AND THEIR THERAPEUTIC USE
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Compounds that may have anti-inflammatory activity are of general formula (I); wherein X1, is H or COR1, and X2 is H or COR2 but X1, and X2are not both H; R1 and R2 are the same or different and are each C1-4 alkyl substituted with R3, or a four to seven-membered ring which can be optionally substituted with R8 and can contain one or more additional heteroatoms selected from O, S(O)n and NR9; is R3 is F, CF3, OR4, NR5R6 O, S(O)n R7 ; R4, R5 and R6 are the same or different and are each H or C1-4 alkyl optionally substituted with R3, or NR5R6 is a C4-6 heterocycloalkyl ring containing one or more heteroatoms selected from O, NR8 and S(O)n; each n is 0-2; R7 is C1-4 alkyl; R8 is as defined for R3 or C1-4 alkyl optionally substituted with R3 or halogen; and R9 is H or C1-4 alkyl; or a salt, solvate or hydrate thereof.
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Page/Page column 9-10
(2008/06/13)
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- Expedient total syntheses of rhein and diacerhein via fries rearrangement
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Short and practical total syntheses of rhein (1) and diacerhein (2) have been achieved via a Fries rearrangement and bis-carbonylation strategy followed by cyclization in molten salt, starting from dibromoester 7.
- Tisserand, Steve,Baati, Rachid,Nicolas, Marc,Mioskowski, Charles
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p. 8982 - 8983
(2007/10/03)
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- Two new anthraquinone derivatives from Rheum emodi
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Two new compounds isolated from rhizomes of Rheum emodi have been characterised as rheinal 1 and rhein-11-O-β-D-glucoside 2 by spectral data and chemical studies.
- Agarwal, Santosh K.,Singh, Sudhir S.,Verma, Sushma,Kumar, Sushil
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p. 749 - 751
(2007/10/03)
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- A new anthraquinone derivative from Cassia fistula Linn, pods
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From the pods of Cassia fistula Linn., an anthraquinone derivative, characterised as 3-formyl-1-hydroxy-8-methoxyanthraquinorie 1, has been isolated. This is the first report on the isolation and characterisation of this compound.
- Rani, Meena
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p. 1314 - 1315
(2007/10/03)
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- Anthraquinones related to rhein inhibit glucose uptake into chondrocytes, a mechanism for anti-osteoarthritis drugs?
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Rhein has been shown to inhibit the uptake of glucose into Ehrlich Ascites tumor cells. In this paper we show that a wide range of anthraquinones related to rhein can also inhibit glucose uptake into chondrocytes, many significantly more than the parent molecule.
- Carney, Stephen L.,Broadmore, Richard J.,Tomlinson, Rosemarie,Kingston, Ann,Gallagher, Peter T.,Owton, W. Martin,Miles, Martin V.,Brunavs, Michael,Smith, Colin W.,Hicks, Terry A.,Dobson, David R.,Steggles, David J.,Ambler, Samantha J.,Halliday, Kelly A.
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p. 817 - 822
(2007/10/03)
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- Pharmaceutical compounds
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Pharmaceutical compounds of the formula STR1 in which R1 and R2 are each hydrogen, hydroxyl, halo, C1-4 alkyl, C1-4 alkoxy, acyloxy, --O-glucoside, optionally substituted phenyl or optionally substituted phenyl-C1-4 alkoxy; R3 is tetrazolyl, or and R4 and R5 are each hydrogen, hydroxy, acyloxy, nitro, C1-4 alkyl, C1-4 alkoxy, halo, optionally substituted phenyl, --SO3 H or --NR'R" where R' and R" are each hydrogen or C1-4 alkyl; provided that when R3 is --CR'R".CHR'"CO2 H or tetrazolyl, R1 and R2 are each hydroxyl, halo, C1-4 alkyl, C1-4 alkoxy, acyloxy, --O-glucoside, optionally substituted phenyl or optionally substituted phenyl C1-4 alkoxy; and or a pharmaceutically acceptable salt or ester thereof.
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- A new synthesis of Rhein
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A novel synthesis of Rhein (2), the active metabolite of the anti-osteoarthritic drug Diacetyl Rhein (1) has been achieved. Key steps include stereospecific olefination of aldehyde 21 with novel phosphonate 28 and the cylisation of acid 31 to produce anthracene 32.
- Gallagher, Peter T.,Hicks, Terry A.,Lightfoot, Andrew P.,Martin Owton
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p. 289 - 292
(2007/10/02)
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- Novel Oxidative Transformation: Regiospecific Preparation of Naturally Occurring 1-Hydroxyanthraquinones
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A brief reaction sequence for synthesis of the naturally occurring anthraquinones 1-hydroxyanthraquinone (4a), 1-hydroxy-2-methylanthraquinone (4b), pachybasin (4c), chrysophanol (5a), and rhein (5c) has been developed.
- Hauser, Frank M.,Prasanna, Subbarao
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p. 383 - 384
(2007/10/02)
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